Dataset Information

On the Question of Uncatalyzed CO Insertion into a Hydrazone Double Bond: A Comparative Study Using Different CO Sources and Substrates.

ABSTRACT: Because of endogenous signaling roles of carbon monoxide (CO) and its demonstrated pharmacological effects, there has been extensive interests in developing fluorescent CO probes. Palladium-mediated CO insertion has been successfully used for such applications. However, recent years have seen many publications of using uncatalyzed CO insertion into a hydrazone double bond as a way to sense CO. Such chemistry has no precedents otherwise. Further, the rigor of the CO-sensing work was largely based on using ruthenium-carbonyl complexes such as CORM-3 as CO surrogates, which have been reported to have extensive chemical reactivity and to release largely CO₂ instead of CO unless in the presence of a strong nucleophile such as dithionite. For all of these, it is important to reassess the feasibility of such a CO-insertion reaction. By studying two of the reported "CO probes" using CO gas, this study finds no evidence of CO insertion into a hydrazone double bond. Further, the chemical reaction between CO gas and a series of eight hydrazone compounds was conducted, leading to the same conclusion. Such findings are consistent with the state-of-the-art knowledge of carbonylation chemistry and do not support uncatalyzed CO insertion as a mechanism for developing fluorescent CO probes.

SUBMITTER: Liu D

PROVIDER: S-EPMC11232009 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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On the Question of Uncatalyzed CO Insertion into a Hydrazone Double Bond: A Comparative Study Using Different CO Sources and Substrates.

Liu Dongning D Bauer Nicola N Lu Wen W Yang Xiaoxiao X Wang Binghe B

The Journal of organic chemistry 20240618 13

Because of endogenous signaling roles of carbon monoxide (CO) and its demonstrated pharmacological effects, there has been extensive interests in developing fluorescent CO probes. Palladium-mediated CO insertion has been successfully used for such applications. However, recent years have seen many publications of using uncatalyzed CO insertion into a hydrazone double bond as a way to sense CO. Such chemistry has no precedents otherwise. Further, the rigor of the CO-sensing work was largely based ...[more]

PMID: 38888488

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Project description:With the recognition of the endogenous signaling roles and pharmacological functions of carbon monoxide (CO), there is an increasing need to understand CO's mechanism of actions. Along this line, chemical donors have been introduced as CO surrogates for ease of delivery, dosage control, and sometimes the ability to target. Among all of the donors, two ruthenium-carbonyl complexes, CORM-2 and -3, are arguably the most commonly used tools for about 20 years in studying the mechanism of actions of CO. Largely based on data using these two CORMs, there has been a widely accepted inference that the upregulation of heme oxygenase-1 (HO-1) expression is one of the key mechanisms for CO's actions. However, recent years have seen reports of very pronounced chemical reactivities and CO-independent activities of these CORMs. We are interested in examining this question by conducting comparative studies using CO gas, CORM-2/-3, and organic CO donors in RAW264.7, HeLa, and HepG2 cell cultures. CORM-2 and CORM-3 treatment showed significant dose-dependent induction of HO-1 compared to "controls," while incubation for 6 h with 250-500 ppm CO gas did not increase the HO-1 protein expression and mRNA transcription level. A further increase of the CO concentration to 5% did not lead to HO-1 expression either. Additionally, we demonstrate that CORM-2/-3 releases minimal amounts of CO under the experimental conditions. These results indicate that the HO-1 induction effects of CORM-2/-3 are not attributable to CO. We also assessed two organic CO prodrugs, BW-CO-103 and BW-CO-111. BW-CO-111 but not BW-CO-103 dose-dependently increased HO-1 levels in RAW264.7 and HeLa cells. We subsequently studied the mechanism of induction with an Nrf2-luciferase reporter assay, showing that the HO-1 induction activity is likely due to the activation of Nrf2 by the CO donors. Overall, CO alone is unable to induce HO-1 or activate Nrf2 under various conditions in vitro. As such, there is no evidence to support attributing the HO-1 induction effect of the CO donors such as CORM-2/-3 and BW-CO-111 in cell culture to CO. This comparative study demonstrates the critical need to consider possible CO-independent effects of a chemical CO donor before attributing the observed biological effects to CO. It is also important to note that such in vitro results cannot be directly extrapolated to in vivo studies because of the increased level of complexity and the likelihood of secondary and/or synergistic effects in the latter.

Dataset Information

On the Question of Uncatalyzed CO Insertion into a Hydrazone Double Bond: A Comparative Study Using Different CO Sources and Substrates.

Publications

On the Question of Uncatalyzed CO Insertion into a Hydrazone Double Bond: A Comparative Study Using Different CO Sources and Substrates.

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